Although human immunodeficiency virus type-1 ("HIV-1") uses the T cell surface molecule CD4 as a primary receptor, successful viral entry into and infection of a cell has been found to require the presence of a second molecule, or "co-receptor" (Clapham and Weiss, 1997, Nature 388:230-231). Seven co-receptor molecules have been identified, each of which are members of, or related to, the family of chemokine receptors, which are G-protein coupled receptors having seven transmembrane domains.
Chemokines are proteins having molecular weights from about 7-16 kDa which, acting as ligands at chemokine receptors, induce a rapid calcium influx and mediate a number of effects on the immune system (Murphy, 1996, Cytokine Growth Factor Rev. 7:47-64). Examples of chemokines include macrophage inflammatory protein ("MIP")-1a and MIP-1b, a protein which is regulated on activation normally .sub.-- cell expressed and secreted ("RANTES"), monocyte chemoattractant protein ("MCP")-1, MCP-2, MCP-3, MCP-4, eotaxin, and stromal-derived factor ("SDF")-1 (Clapham and Weiss, 1997, Nature 388:230-231). Chemokines are proteins that are classified into two groups based on the presence of a non-cysteine amino acid ("X") between the first two ("CC") of four cysteine residues appearing in their amino acid sequence, giving rise to the CXC (cc) family and the CC (D) family. Receptors which specifically recognize CXC or CC chemokines are referred to, accordingly, as CXCR or CCR ("Dynamics of HIV Infection", Science and Medicine, March/April 1998: 36-45).
Two species of chemokine receptors which appear to be particularly relevant to HIV infection are CCR5 and CXCR4, for which the natural ligands are MIP-1a, MIP-1b and RANTES (CCR5) and SDF-1 (CXCR4). To date, most HIV-1 clinical isolates appear to use CCR5 or CXCR4, or both, as co-receptors with CD4 for entry into cells ("Dynamics of HIV Infection", Science and Medicine, March/April 1998: 36-45), and the presence of chemokine ligand inhibits infection via the corresponding receptor.
The cellular distributions of CCR5 and CXCR4 are associated with the role of these molecules in the course of HIV-1 infection. CCR5 (Samson et al., 1996, Biochemistry 35:3362-3367), which is mainly expressed on macrophages and memory T cells, serves as a co-receptor for infection by macrophage-tropic ("M-tropic") strains of HIV-1, which are found throughout the course of infection, are preferentially involved in sexual transmission of HIV-1, and are represented by non-syncytium-inducing laboratory isolates which do not cause cell/cell fusion in T cell lines ("Dynamics of HIV Infection", Science and Medicine, March/April 1998: 36-45; Cocchi et al., 1995, Science 270:1811-1815; Alkhatib et al., 1996, Science 272:1955-1958; Choe et al., 1996, Cell 85:1135-1148; Deng et al., 1996, Nature 381:661-666; Doranz et al., 1996, Cell 85:1149-1158; Dragic et al., 1996, Nature 381:667-673). CXCR4, however, which is expressed on a broader spectrum of cells, including naive T cells, serves as the co-receptor in late stages of infection for syncytium-inducing, T-cell-tropic ("T-tropic") strains of HIV-1 (Bleul et al., 1996, Nature 382: 829-833; Oberlin et al., 1996, Nature 382: 833-835; Feng et al., 1996, Science 272:872-877). Accordingly, the co-receptor which is more relevant to the initiation of HIV-1 infection appears to be CCR5.
Indeed, an association has been drawn between those rare individuals who remain persistently uninfected despite multiple sexual exposures to HIV and the presence of a 32 base pair deletion in the CCR5 gene ("CCR5.DELTA.32"; Samson et al., 1996, Nature 382:722-725; Liu et al., 1996, Cell 86:367) which results in a frame shift mutation and the loss of the last three of the seven transmembrane domains (including the fifth, sixth and seventh transmembrane domains) present in the wild-type protein. Individuals heterozygous for this deletion, are, however, susceptible to infection (Dean et al., Science 273:1856), although progression to AIDS may be slowed (Dean et al., 1996, Science 273:1856-1862; Samson et al., 1996, Nature 382:722-725; Huang et al., 1996, Nature Med. 2:1240-1243; Michael et al., 1997, Nature Med. 3:338-340). It has been proposed (Benkirane et al., December 1997, J. Biol. Chem. 272:30603-30606) that co-expression of the CCR5.DELTA.32 gene with the wild-type CCR5 gene results in trans-inhibition of the ability of CCR5 to act as an HIV co-receptor, in which the CCR5.DELTA.32 protein interferes with dimerization of CCR5 at the cell surface. It has not, however, been confirmed that dimerization of CCR5 occurs or is necessary for viral entry.